We identified, isolated characterized biochemically, cloned and sequenced cDNA from mRNA encoding the oligodendrocyte-myelin glycoprotein (OMgp) and cloned and sequenced the gene encoding OMgp. OMgp is a heavily glycosylated glycoprotein confined to myelin and cells of oligodendrocyte and Schwann cell lineages. It is bound to membranes with a glycosylphosphatidylinositol linkage and can therefore be released from the membrane through the activation of a phospholipase. The deduced primary structure of the protein has a cysteine-rich 32 amino acid domain at the N- terminus, followed by a contiguous domain of 7 1/2 leucine-rich repeats of 24 amino acids each and a domain of 4 1/2 repeats of 40 amino acids rich in serines and threonines. At the C-terminus there is a hydrophobic domain which most likely serves as the attachment site for the glycolipid tail. There are eight other proteins which share with OMgp the cysteine-rich N- terminal domain and the contiguous domain of leucine-rich repeats. In addition, the structure of the gene for OMgp is almost identical to the structure of the gene encoding one of the other proteins in this group. On the basis of this we have suggested that these proteins should be classified together as a family of proteins, the CR-LR family. In this application we propose to search for ligands for OMgp in both the CNS and the PNS. We also propose to work out the mechanism of the difference in the control of expression of OMgp in cells of CNS versus PNS origin. This may help us to understand the differences between oligodendrocytes and Schwann cells which in turn could help explain the selective involvement of the CNS in multiple sclerosis. Such knowledge could be the key to understanding the pathogenesis of multiple sclerosis. In addition, we propose to generate transgenic mice with over-expression or aberrant expression of OMgp as well as transgenic mice expressing OMGp without the membrane-linkage, which theoretically could compete with the membrane-bound protein or ligands. Our goal in these studies is not only to increase our understanding of the biological role of OMgp but also our understanding of the myelin-forming cells and of diseases that affect them.